Pharmacokinetics of Amitriptyline Demethylation;A Crossover Study with Single Doses of Amitriptyline and Nortriptyline

A single dose crossover pharmacokinetic study of amitriptyline and nortriptyline was done to find out the extent of first-pass metabolism to nortriptyline after amitripyline administration, and the contribution of nortriptyline during amitriptyline therapy. Six healthy male volunteers took part in this study and were given single doses (50 mg) of amitriptyline and nortriptyline at more than three-week intervals. Plasma concentrations of the drugs were measured up to 48 hours. Total area under the plasma concentration-time curve (AUe) of amitriptyline (744.6±258.4 ng/ml·hl was smaller than that of nortriptyline (l497.3±589.8 ng/ml'h), and the mean terminal half-life of amitriptyline (21.8±3.9 hr) was shorter than that of nortriptyline (36.8±5.9 h). The total area under the plasma concentration-time curve of nortriptyline produced by amitriptyline administration was 498.1 ±274.5 ng/ml·h, and the fraction produced by the first-pass of amitriptyline was 33.7 ± 10.5%. From this data, it can be estimated that the average nortriptyline concentration could be about 40% of the total tricyclic antidepressants present in the plasma of patients taking multiple amitriptyline therapy at steady state. About 34% of nortriptyline is produced by first- pass effect during gastrointestinal absorption of amitriptyline to systemic circulation resulting from N-demethylation of amitriptyline in the liver. Then, the rest of the nortriptyline is formed continuously at a rate proportional to the rate of amitriptyline elimination

Identification of new CYP2C19 variants exhibiting decreased enzyme activity in the metabolism of S-mephenytoin and omeprazole. Drug Metab

ABSTRACT: Although many cases of interindividual variation in the metabolism of CYP2C19 drugs are explained by the CYP2C19*2, *3, and *17, a wide range of metabolic variation still occurs in people who do not carry these genetic variants. The objectives of this study were to identify new genetic variants and to characterize functional consequences of these variants in metabolism of CYP2C19 substrates. In total, 21 single-nucleotide polymorphisms including three new coding variants, V394M, E405K, and D256N, were identified by direct DNA sequencing in 50 randomly selected subjects and in individuals who exhibited an outlier phenotype response in the omeprazole study. Recombinant proteins produced from the coding variants V394M, E405K, and D256N were prepared by using an Escherichia coli expression system and purified. Metabolism of S-mephenytoin and omeprazole by V394M was comparable with that of the wild-type protein. E405K showed a moderate decrease in metabolism of the substrates. However, D256N exhibited a significantly decreased activity in S-mephenytoin metabolism, resulting in 50 and 76% decreases in V max and intrinsic clearance, respectively, compared with the wild type. This variant also exhibited a significant decrease in omeprazole metabolism in vivo. CYP2C19 D256N and E405K were assigned as CYP2C19*26 and *2D, respectively, by the Cytochrome P450 Nomenclature Committee. In summary, this report characterizes the allele frequency and haplotype distribution of CYP2C19 in a Korean population and provides functional analysis of new coding variants of the CYP2C19 gene. Our findings suggest that individuals carrying CYP2C19*26 would have lower activity for metabolizing CYP2C19 substrate drugs

Rifampin enhances cytochrome P450 (CYP) 2B6-mediated efavirenz 8-hydroxylation in healthy volunteers

The effect of rifampin on the in vivo metabolism of the antiretroviral drug efavirenz was evaluated in healthy volunteers. In a cross-over placebo control trial, healthy subjects (n = 20) were administered a single 600 mg oral dose of efavirenz after pretreatment with placebo or rifampin (600 mg/day for 10 days). Plasma and urine concentrations of efavirenz, 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz were measured by LC-MS/MS. Compared to placebo treatment, rifampin increased the oral clearance (by ∼2.5-fold) and decreased maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-∞) of efavirenz (by ∼1.6- and ∼2.5-fold respectively) (p < 0.001). Rifampin treatment substantially increased the Cmax and AUC0-12h of 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz, metabolic ratio (AUC0-72h of metabolites to AUC0-72h efavirenz) and the amount of metabolites excreted in urine (Ae0-12hr) (all, p < 0.01). Female subjects had longer elimination half-life (1.6-2.2-fold) and larger weight-adjusted distribution volume (1.6-1.9-fold) of efavirenz than male subjects (p < 0.05) in placebo and rifampin treated groups respectively. In conclusion, rifampin enhances CYP2B6-mediated efavirenz 8-hydroxylation in vivo. The metabolism of a single oral dose of efavirenz may be a suitable in vivo marker of CYP2B6 activity to evaluate induction drug interactions involving this enzyme

Discovery of a novel allelic variant of CYP2C8, CYP2C8∗11, in asian populations and its clinical effect on the rosiglitazone disposition

ABSTRACT: The objectives of this study were to identify the genetic variants of CYP2C8, analyze CYP2C8 single nucleotide polymorphisms (SNPs), and characterize their functional consequences in the CYP2C8 substrate drug rosiglitazone in humans. The direct full sequencing of CYP2C8 genomic DNA was performed in a Korean population (n ‫؍‬ 50). A total of 17 CYP2C8 variants including a novel coding variant (E274Stop) were identified. The novel CYP2C8 E274Stop variant was assigned as CYP2C8*11 by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee. Seventeen SNPs were used to characterize linkage disequilibrium, haplotype structures, and haplotype tagging SNPs. Genotyping for CYP2C8*11 in an extended set of Koreans (n ‫؍‬ 400), whites (n ‫؍‬ 100), Han Chinese (n ‫؍‬ 348), Vietnamese (n ‫؍‬ 100), and African Americans (n ‫؍‬ 93) was performed by a newly developed pyrosequencing method. The frequency of CYP2C8*11 was 0.3% in Koreans, 1% in Vietnamese, and 0.14% in Chinese. However, none of the whites or African Americans contained the CYP2C8*11 allele. Subjects with CYP2C8*1/*11 exhibited higher plasma concentration-time profiles of rosiglitazone than those of nine control subjects carrying CYP2C8*1/*1. The area under the concentrationtime curve and peak plasma concentration of rosiglitazone in individuals carrying CYP2C8*1/*11 (n ‫؍‬ 5) were 54 and 34% higher than the mean values observed in the control subjects carrying CYP2C8*1/*1 (P ‫؍‬ 0.015 and P ‫؍‬ 0.025, respectively). In summary, this is the first report to characterize the allele frequency and haplotype distribution of CYP2C8 in a Korean population, and it provides functional analysis of a new variant CYP2C8*11. Our findings suggest that individuals carrying CYP2C8*11, a null allele found in Asians only, may have lower activity for metabolizing CYP2C8 substrate drugs

Alterations of lipid-related genes during anti-tuberculosis treatment: insights into host immune responses and potential transcriptional biomarkers

BackgroundThe optimal diagnosis and treatment of tuberculosis (TB) are challenging due to underdiagnosis and inadequate treatment monitoring. Lipid-related genes are crucial components of the host immune response in TB. However, their dynamic expression and potential usefulness for monitoring response to anti-TB treatment are unclear. MethodologyIn the present study, we used a targeted, knowledge-based approach to investigate the expression of lipid-related genes during anti-TB treatment and their potential use as biomarkers of treatment response. Results and discussionThe expression levels of 10 genes (ARPC5, ACSL4, PLD4, LIPA, CHMP2B, RAB5A, GABARAPL2, PLA2G4A, MBOAT2, and MBOAT1) were significantly altered during standard anti-TB treatment. We evaluated the potential usefulness of this 10-lipid-gene signature for TB diagnosis and treatment monitoring in various clinical scenarios across multiple populations. We also compared this signature with other transcriptomic signatures. The 10-lipid-gene signature could distinguish patients with TB from those with latent tuberculosis infection and non-TB controls (area under the receiver operating characteristic curve &gt; 0.7 for most cases); it could also be useful for monitoring response to anti-TB treatment. Although the performance of the new signature was not better than that of previous signatures (i.e., RISK6, Sambarey10, Long10), our results suggest the usefulness of metabolism-centric biomarkersConclusionsLipid-related genes play significant roles in TB pathophysiology and host immune responses. Furthermore, transcriptomic signatures related to the immune response and lipid-related gene may be useful for TB diagnosis and treatment monitoring

Pharmacogenetics Meets Metabolomics: Discovery of Tryptophan as a New Endogenous OCT2 Substrate Related to Metformin Disposition

Genetic polymorphisms of the organic cation transporter 2 (OCT2), encoded by SLC22A2, have been investigated in association with metformin disposition. A functional decrease in transport function has been shown to be associated with the OCT2 variants. Using metabolomics, our study aims at a comprehensive monitoring of primary metabolite changes in order to understand biochemical alteration associated with OCT2 polymorphisms and discovery of potential endogenous metabolites related to the genetic variation of OCT2. Using GC-TOF MS based metabolite profiling, clear clustering of samples was observed in Partial Least Square Discriminant Analysis, showing that metabolic profiles were linked to the genetic variants of OCT2. Tryptophan and uridine presented the most significant alteration in SLC22A2-808TT homozygous and the SLC22A2-808G>T heterozygous variants relative to the reference. Particularly tryptophan showed gene-dose effects of transporter activity according to OCT2 genotypes and the greatest linear association with the pharmacokinetic parameters (Clrenal, Clsec, Cl/F/kg, and Vd/F/kg) of metformin. An inhibition assay demonstrated the inhibitory effect of tryptophan on the uptake of 1-methyl-4-phenyl pyrinidium in a concentration dependent manner and subsequent uptake experiment revealed differential tryptophan-uptake rate in the oocytes expressing OCT2 reference and variant (808G>T). Our results collectively indicate tryptophan can serve as one of the endogenous substrate for the OCT2 as well as a biomarker candidate indicating the variability of the transport activity of OCT2

NICE 2023 Zero-shot Image Captioning Challenge

In this report, we introduce NICE project\footnote{\url{https://nice.lgresearch.ai/}} and share the results and outcomes of NICE challenge 2023. This project is designed to challenge the computer vision community to develop robust image captioning models that advance the state-of-the-art both in terms of accuracy and fairness. Through the challenge, the image captioning models were tested using a new evaluation dataset that includes a large variety of visual concepts from many domains. There was no specific training data provided for the challenge, and therefore the challenge entries were required to adapt to new types of image descriptions that had not been seen during training. This report includes information on the newly proposed NICE dataset, evaluation methods, challenge results, and technical details of top-ranking entries. We expect that the outcomes of the challenge will contribute to the improvement of AI models on various vision-language tasks.Comment: Tech report, project page https://nice.lgresearch.ai